Parathyroid Hormone Receptors
The parathyroid hormone receptors (PTH receptors) are part of an extended family of receptors. Usdin, et al., J Biol Chem 270:15455–15458 (1995). The human parathyroid hormone type 2 receptor (PTH2 receptor) shares about 51% amino-acid sequence identity with the human parathyroid hormone type 1 receptor (PTH1 receptor). Both PTH receptors belong to the Type II family of G-protein-coupled receptors which respond to peptide modulators, including calcitonin, glucagon, secretin and vasoactive intestinal polypeptide. Both PTH receptors are activated by PTH, but only the PTH1 receptor is activated by parathyroid hormone-related protein (PTHrP). The PTH2 and PTH1 receptors, together with their ligands, have presumably evolved to selectively mediate different physiological functions.
Parathyroid Hormone 2 Receptor
The PTH2 receptor is a G-protein coupled receptor selectively activated by parathyroid hormone (PTH) and not by PTHrP. The first demonstration of this was by Usdin et al. (J Biol Chem 270:15455–15458 (1995)) and later by Behar et al. (Endocrinology 137:2748–57 (1996)) and Gardella et al. (J Biol Chem 271:19888–19893 (1996)). It is most similar in sequence and ligand recognition specificity to the PTH1 receptor (also called the PTH/PTHrP receptor). Abou-Samra, et al., Cell Biology 89:2732–2736 (1992); Juppner, et al., Science 254:1024–1026 (1991). Prior to discovery of the PTH2 receptor, studies of PTH action had not predicted the existence of the PTH2 receptor.
Recent work implies a significant role of the PTH2 receptor in regulating a number of diverse physiological processes. In view of this work it is clear that identifying the endogenous ligand that binds to and activates the PTH2 receptor is extremely important and may provide a therapeutic vehicle with which to treat a number of metabolic disorders. Antagonists of the PTH2 receptor would also have therapeutic importance as agents for modulating PTH2 receptor function.
Parathyroid Hormone 1 Receptor
The parathyroid hormone type 1 receptor (PTH1 receptor) mediates the principal physiological responses to PTH and to PTH-related protein (PTHrP). Potts et al., in Williams' Textbook of Endocrinology, pp. 920–966 (1995). PTH is involved in the regulation of calcium homeostasis, in that the hormone acts on the PTH1 receptor in bone and kidney to elevate blood calcium levels. PTHrP is a locally-acting autocrine/paracrine factor and developmental regulator. Both of these peptides are involved in disorders of calcium metabolism. In humoral hypercalcaemia of malignancy (HHM) certain tumors produce very high levels of PTHrP, leading to activation of the PTH1 receptor and elevation of blood calcium levels. Grill et al., European Journal of Cancer 34:222–229 (1998). In primary hyperparathyroidism (HPT), elevated blood calcium levels results from excessive secretion of PTH from a parathyroid gland. Nemeth and Fox, Trends Endocrinol Metab 10:66–71 (1999). In secondary and tertiary HPT, chronic renal failure leads to reduced calcium levels, morphological changes of the parathyroid gland and elevated PTH secretion. Slatopolsky et al., Kidney Int Suppl 73:S14–9 (1999). The PTH1 receptor is also involved in regulating phosphate homeostasis. Since activation of the PTH1 receptor is involved in these disorders, antagonism of the effects of PTH or PTHrP on the receptor may be of therapeutic utility.